The long-term goal of this revised project is to define the molecular bases for genetic contributions to the development of alcoholism. The immediate goal is to map and measure the contributions of individual gene loci, or QTL (quantitative trait loci), to the behavioral correlates of high ethanol intake and preference in Fawn-Hooded (FH)-derived rats. It has been well established that the standard linkage analysis using human family samples has little power to detect genetic linkage for psychiatric disorders. At the same time, detecting QTLs in animals and plants has become a routine practice. Therefore, we propose to map and measure the effects of individual genes, or QTL, influencing FH/Wjd rat behavioral traits in a cross between FH/Wjd rats with high ethanol intake and preference and a strain exhibiting low intake and preference (ACI/N). We have produced and phenotyped 612 F2s, 36 F1s, and 30 progenitor rats for alcohol intake and preference. Tissue samples (liver, spleen, brain, and kidney) have been preserved and stored from all of these animals. This sample is a valuable resource and has the potential to produce important results. Therefore, in this application, we are asking for funds to do genotyping and data analysis to explore (R21 mechanism) and identify new alcohol-related QTLs. This will be accomplished by collecting data on measuring molecular marker genotypes spaced throughout the rat genome in a F2 intercross population with extreme phenotypes formed by crossing an alcohol-preferring inbred rat strain (FH/Wjd) and an alcohol non-preferring inbred strain (ACI/N). Interval mapping will be used to map and measure the effects of QTLs in this intercross. Potential candidate genes within the intervals found to contain QTLs will be identified by comparative gene mapping and by scoring molecular polymorphisms for candidate genes in the intercross generation. Candidate gene polymorphisms will be included with the micro satellites in a fine scale mapping (by means of Advanced Intercross Lines) of potential QTL locations. The location of genes affecting alcohol related traits in rat genome will help to identify the systemic regions with similar effects in human genome. Finally, the identification of alcoholism-related genes will help to define their roles in the development of severe alcoholism.